Piperidyl amides as novel, potent and orally active mGlu5 receptor antagonists with anxiolytic-like activity

Carsten Spanka; Ralf Glatthar; Sandrine Desrayaud; Markus Fendt; David Orain; Thomas Troxler; Ivo Vranesic

doi:10.1016/j.bmcl.2009.11.001

Piperidyl amides as novel, potent and orally active mGlu5 receptor antagonists with anxiolytic-like activity

Bioorg Med Chem Lett. 2010 Jan 1;20(1):184-8. doi: 10.1016/j.bmcl.2009.11.001. Epub 2009 Nov 5.

Authors

Carsten Spanka¹, Ralf Glatthar, Sandrine Desrayaud, Markus Fendt, David Orain, Thomas Troxler, Ivo Vranesic

Affiliation

¹ Novartis Institutes for Biomedical Research, Global Discovery Chemistry, Basel CH-4002, Switzerland.

PMID: 19931453
DOI: 10.1016/j.bmcl.2009.11.001

Abstract

High throughput screening led to the identification of nicotinamide derivative 2 as a structurally novel mGluR5 antagonist. Optimization of the modular scaffold led to the discovery of 16m, a compound with high affinity for mGluR5 and excellent selectivity over other glutamate receptors. Compound 16m exhibits a favorable PK profile in rats, robust anxiolytic-like effects in three different animal models of fear and anxiety, as well as a good PK/PD correlation.

MeSH terms

Administration, Oral
Amides / chemical synthesis
Amides / chemistry*
Amides / pharmacokinetics
Aminopyridines / chemical synthesis
Aminopyridines / chemistry*
Aminopyridines / pharmacokinetics
Animals
Anti-Anxiety Agents / chemical synthesis
Anti-Anxiety Agents / chemistry*
Anti-Anxiety Agents / pharmacokinetics
Humans
Microsomes, Liver / metabolism
Peptides / chemistry*
Rats
Rats, Sprague-Dawley
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate / antagonists & inhibitors*
Receptors, Metabotropic Glutamate / metabolism
Structure-Activity Relationship

Substances

Amides
Aminopyridines
Anti-Anxiety Agents
GRM5 protein, human
Grm5 protein, rat
Peptides
Receptor, Metabotropic Glutamate 5
Receptors, Metabotropic Glutamate